# US 9,433,611 B2 · Oxazole and thiazole compounds as β-catenin modulators and uses thereof

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- Number: US 9,433,611 B2
- Document ID: US9433611B2
- Status: Granted
- Kind: B2
- Application number: 13/595,336
- Filed: 2012-08-27
- Published: 2013-05-02
- Granted: 2016-09-06
- Earliest claimed: 2008-01-28
- Assignees: New York University
- Applicants: Ramanuj Dasgupta; Foster Gonsalves
- Inventors: Ramanuj Dasgupta; Foster Gonsalves
- Web page: https://patentgrep.com/patent/US9433611B2

## CPC

- A61K 31/421: 1,3-Oxazoles, e.g. pemoline, trimethadione
- A61K 31/4025: not condensed and containing further heterocyclic rings, e.g. cromakalim
- A61K 31/422: not condensed and containing further heterocyclic rings
- A61K 31/426: 1,3-Thiazoles
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/428: condensed with carbocyclic rings
- A61K 31/433: Thidiazoles
- A61K 31/435: having six-membered rings with one nitrogen as the only ring hetero atom
- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/4725: containing further heterocyclic rings
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/498: Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/5415: ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A series of oxazole and thiazole compounds are shown herein to be small molecule inhibitors of the Wnt pathway that specifically target the activity of the stabilized pool of β-cat oxazole and thiazole compounds are disclosed that have a formula represented by the following: The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, cancer, and others.

## Claims

### Claim 1

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound according to formula I:
wherein A is A1;
A1 is
x is 1;
L1 is S, SO or SO2;
m1 is 1, 2 or 3; n is 1, 2, 3, 4 or 5;
each R1, R2a, R2b, R2c, and R2d is independently selected from hydrogen, halo, and substituted or unsubstituted C1-C6 alkyl;
R3 is NR3aR3b; and
one of R3a and R3b is substituted or unsubstituted alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenethyl, cycloheptyl, cyclohexyl, cyclohexyl substituted with methyl or dimethyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclobutyl, or substituted or unsubstituted cyclopropyl; and the other is H or substituted or unsubstituted alkyl; or
NR3aR3b is:
and wherein R3c is H or alkyl;
each R4 is independently selected from alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted sulfinyl, substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thiol; and
a pharmaceutically acceptable salt, solvate or prodrug thereof;
and stereoisomers, isotopic variants and tautomers thereof.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1 wherein the carrier is a parenteral carrier, oral or topical carrier.

### Claim 3 (depends on 1)

The pharmaceutical composition according to claim 1, wherein the compound is according to formula Ha:
and wherein L1, m1, n, R1, R2a, R2b, R2c, R2d, R3, and R4, are as in claim 1.

### Claim 4 (depends on 3)

The pharmaceutical composition according to claim 3, wherein R1 is H, halo, or substituted or unsubstituted C1-C6 alkyl.

### Claim 5 (depends on 3)

The pharmaceutical composition according to claim 3, wherein R3 is NR3aR3b; and;
one of R3a and R3b is substituted or unsubstituted alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenethyl, cycloheptyl, cyclohexyl, cyclohexyl substituted with methyl or dimethyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclobutyl, or substituted or unsubstituted cyclopropyl; and the other is H.

### Claim 6 (depends on 3)

The pharmaceutical composition according to claim 3, wherein R3 is NR3aR3b; and
NR3aR3b is:
and wherein R3c is H or alkyl.

### Claim 7 (depends on 1)

The pharmaceutical composition according to claim 1, wherein the compound is according to formula IVa:
wherein n, and R4 are as in claim 1; and
one of R3a and R3b is substituted or unsubstituted alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenethyl, cycloheptyl, cyclohexyl, cyclohexyl substituted with methyl or dimethyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclobutyl, or substituted or unsubstituted cyclopropyl; and the other is H; or
NR3aR3b is:
and wherein R3c is H or alkyl.

### Claim 8 (depends on 7)

The pharmaceutical composition according to claim 7, wherein n is 1; and R4 is alkyl, alkoxy, or haloalkyl.

### Claim 9 (depends on 7)

The pharmaceutical composition according to claim 7, wherein one of R3a and R3b is substituted or unsubstituted benzyl, substituted or unsubstituted phenethyl, cycloheptyl, cyclohexyl, cyclohexyl substituted with methyl or dimethyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclobutyl, or substituted or unsubstituted cyclopropyl; and the other is H.

### Claim 10 (depends on 1)

The pharmaceutical composition according to claim 1, wherein the compound is according to formula VIIa, VIIb, VIIc or VIId:
wherein R3b is substituted or unsubstituted alkyl, benzyl, substituted or unsubstituted phenethyl, cyclohexyl, cyclohexyl substituted with methyl or dimethyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclobutyl, or substituted or unsubstituted cyclopropyl.

### Claim 11 (depends on 1)

The pharmaceutical composition according to claim 1, wherein the compound is according to formula VIIIa, VIIIb, VIIIc, or VIIId:
wherein Cy is
and wherein R3c is H or alkyl.

### Claim 12 (depends on 1)

The pharmaceutical composition according to claim 1, wherein the compound is according to formula XIIa, XIIb, XIIc or XIId:

### Claim 13 (depends on 1)

The pharmaceutical composition according to claim 1, wherein the compound is according to formula XIIIa, XIIIb, XIIIc or XIIId:

### Claim 14

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, wherein the compound is according to formula XIa, XIb, XIc or XId:

### Claim 15

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, wherein the compound is selected from Table 1.

### Claim 16

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, wherein the compound is selected from Table 2.

### Claim 17

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, wherein the compound is selected from Table 4.

### Claim 18

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound according to formula I:
wherein A is A1;
A1 is
x is 1;
L1 is S, SO or SO2;
m1 is 1, 2 or 3; n is 1, 2, 3, 4 or 5;
each R1, R2a, R2b, R2c, and R2d is independently selected from hydrogen, halo, and substituted or unsubstituted C1-C6 alkyl;
R3 is NR3aR3b; and
one of R3a and R3b is substituted or unsubstituted alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenethyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclobutyl, or substituted or unsubstituted cyclopropyl; and the other is H or substituted or unsubstituted alkyl; or
NR3aR3b is:
and wherein R3c is H or alkyl;
each R4 is independently selected from alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted sulfinyl, substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thiol; and
a pharmaceutically acceptable salt, solvate or prodrug thereof;
and stereoisomers, isotopic variants and tautomers thereof.